The objective of the proposed studies is to elucidate the mechanism of action of commonly used general anesthetics on excitable membranes. These studies will be conducted under different conditions of atmospheric pressure and temperature. Voltage-clamp, internal perfusion and radio-active tracer techniques will be used to measure changes in electrical properties of squid and myxicola giant axons caused by anesthetics. Our previous studies have clearly shown that low concentrations of general anesthetics greatly increase the resting sodium permeability and the ion selectivity ratio (PK/PNa) of the sodium channel during activity of squid axon. These changes in electrical properties reduce peak sodium current thereby blocking nerve conduction, and are quite likely to occur in small nerve fibers and endings in the brain, during general anesthesia. In this proposal, we plan to study in detail a) the changes by anesthetics in the resting membrane permeabilities to various ions; b) the changes in permeabilities of the sodium channel to various ions during activity, and c) the effects of pressure and temperature on these anesthetic induced changes. Since the increased pressure and temperature are known to influence the anesthetic action, the proposed studies are expected to clarify the nature of interactions between anesthetic molecules and membrane ionic channels.